Abstract

Background

Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also
shown how components of the insulin and target of rapamycin (TOR) pathways are key
regulators of growth. Despite a few suggestions that Myc transcriptional activity
lies downstream of these pathways, a molecular mechanism linking these signaling pathways
to Myc has not been clearly described. Using biochemical and genetic approaches we
tried to identify novel mechanisms that control Myc activity upon activation of insulin
and TOR signaling pathways.

Results

Our biochemical studies show that insulin induces Myc protein accumulation in Drosophila S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase
3-beta (GSK3β ) a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin
is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced
Myc protein accumulation depends on the activation of TOR complex 1. Treatment with
amino acids that directly activate the TOR pathway results in Myc protein accumulation,
which also depends on the ability of S6K kinase to inhibit GSK3β activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in
cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces
Myc protein accumulation, while inhibition of insulin and TOR pathways result in the
opposite effect. Our functional analysis, aimed at quantifying the relative contribution
of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that
Myc activity is necessary to sustain the proliferation of cells from the ommatidia
upon Dp110 expression, while its contribution downstream of TOR is significant to
control the size of the ommatidia.

Conclusions

Our study presents novel evidence that Myc activity acts downstream of insulin and
TOR pathways to control growth in Drosophila. At the biochemical level we found that both these pathways converge at GSK3β to control Myc protein stability, while our genetic analysis shows that insulin and
TOR pathways have different requirements for Myc activity during development of the
eye, suggesting that Myc might be differentially induced by these pathways during
growth or proliferation of cells that make up the ommatidia.